Use of anisodamine hydrobromide in preparing a drug for preventing and / or treating cisplatin ototoxicity

Abstract

The present invention provides the use of anisodamine hydrobromide in preparing a drug for preventing and / or treating cisplatin ototoxicity, and belongs to the field of medicine. The present invention first finds that anisodamine hydrobromide tablets can significantly improve ototoxicity caused by cisplatin, improve hearing impairment, promote blood flow, and inhibit oxidative stress, and anisodamine hydrobromide injection can improve ototoxic hearing damage caused by cisplatin, and has anti-inflammatory and cochlear hair cell protection effects. Anisodamine hydrobromide has broad application prospects in preparing drugs for preventing and / or treating cisplatin ototoxicity.

Description

Technical Field

[0001] The invention belongs to the field of medicine, and particularly relates to use of anisodamine hydrobromide in preparing a medicine for preventing and / or treating cisplatin ototoxicity. Background Art

[0002] Cisplatin (Cis) is a commonly used anti-tumor drug that has significant therapeutic effects on a variety of solid tumors including bladder cancer, ovarian cancer, testicular cancer, head and neck cancer, lung cancer, etc. It is the first-line drug for most current chemotherapy regimens. Studies have reported that the incidence of cisplatin ototoxicity is high, and irreversible sensorineural hearing loss occurs during cisplatin treatment, which limits its clinical application. Cisplatin ototoxicity is one of its main side effects. Compared with other ototoxic drugs, cisplatin not only causes vestibular dysfunction, but also leads to hearing loss, and can develop into bilateral irreversible sensorineural hearing loss. The ototoxicity of cisplatin mainly damages the inner ear, induces apoptosis of hair cells, and then causes hearing loss and balance dysfunction. At present, there is no drug that can treat cisplatin ototoxicity in clinical practice, and the development of drugs to treat cisplatin ototoxicity is of great significance.

[0003] Anisodamine hydrobromide (ANI HBr) is an M receptor blocker with multiple pharmacological effects, including calcium antagonism, antioxidant effects, increased cell membrane fluidity, and microcirculation regulation. ANI HBr is a commonly used drug in clinical practice and is often used for internal medicine diseases, including pancreatitis, renal colic, septic shock, etc. There are currently no reports on the use of anisodamine hydrobromide to treat cisplatin ototoxicity. Summary of the invention

[0004] The purpose of the present invention is to provide the therapeutic effect of anisodamine hydrobromide in cisplatin ototoxicity.

[0005] The present invention provides use of anisodamine hydrobromide in preparing a medicine for preventing and / or treating cisplatin ototoxicity.

[0006] Furthermore, the drug is a pharmaceutical preparation prepared with anisodamine hydrobromide as an active ingredient and pharmaceutically acceptable excipients.

[0007] Furthermore, the pharmaceutical preparation is an oral preparation or an injection preparation.

[0008] Furthermore, the oral preparation is a tablet, a granule, or a capsule.

[0009] Furthermore, the injection preparation is an injection solution or a powder injection.

[0010] The present invention first discovered that anisodamine hydrobromide tablets can significantly improve ototoxicity caused by cisplatin, improve hearing impairment, promote blood flow, and inhibit oxidative stress, and anisodamine hydrobromide injection can improve hearing damage caused by cisplatin ototoxicity, resist inflammation, and protect cochlear hair cells. Anisodamine hydrobromide has broad application prospects in the preparation of drugs for preventing and / or treating cisplatin ototoxicity.

[0011] Obviously, according to the above contents of the present invention, in accordance with common technical knowledge and customary means in the art, without departing from the above basic technical ideas of the present invention, other various forms of modification, replacement or change may be made.

[0012] The above contents of the present invention are further described in detail below through specific implementation methods in the form of examples. However, this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figure 1 The behavioral effects of Ani HBr on cisplatin-induced ototoxicity in guinea pigs (A: head shaking times; B: nystagmus times; C: head deviation; D: air righting reflex; E: negative geotropism. Values ​​are mean ± SD (n = 8). Compared with the control group (Control), # p<0.05, ## p<0.01, * p<0.05, ** p<0.01 compared with the model group (Cisplatin)).

[0014] Figure 2 The effect of Ani HBr on blood flow in guinea pigs with ototoxicity induced by cisplatin (A: gray matter image, pseudo-color image; B: relative blood flow change. Values ​​are mean ± SD (n = 8). Compared with the control group (Control), # p<0.05, ## p<0.01, * p<0.05, ** p<0.01 compared with the model group (Cisplatin)).

[0015] Figure 3 This is the ABR detection curve of guinea pigs (A: Control group; B: Cisplatin group; C: Betahistine group; D: L-Ani HBr; E: M-Ani HBr; F: H-Ani HBr).

[0016] Figure 4This is the CAP detection curve of guinea pigs (A: Control group; B: Cisplatin group; C: Betahistine group; D: L-Ani HBr; E: M-Ani HBr; F: H-Ani HBr).

[0017] Figure 5 A: ABR latency; B: ABR threshold; C: CAP threshold of guinea pigs in different groups.

[0018] Figure 6 The DPOAE thresholds of guinea pigs in each group (A: 4kHZ, DPOAE threshold; B: 8kHZ, DPOAE threshold; C: 16kHZ, DPOAE threshold; D: 32kHZ, DPOAE threshold. Values ​​are mean ± SD (n = 8 / group). Compared with the control group (Control), # p<0.05, ## p<0.01, * p<0.05, ** p<0.01 compared with the cisplatin group).

[0019] Figure 7 Effects of Ani HBr on serum indicators of cisplatin-induced ototoxicity in guinea pigs (A: T-SOD content; B: glutathione content; C: MDA concentration. Values ​​are mean ± SD (n = 8). Compared with the control group (Control), # p<0.05, ## p<0.01, * p<0.05, ** p<0.01 compared with the cisplatin group).

[0020] Figure 8 Scoring of rat behavior (tail hanging reflex, balance beam, head deviation, nystagmus) * p<0.05, ** p<0.005, *** p<0.0005, # represents the comparison between Cis group and Control group).

[0021] Fig. 9 is the total behavioral score of rats ( * p<0.05, ** p<0.005, *** p<0.0005, # represents the comparison between Cis group and Control group).

[0022] Fig.10 The bar graph of the hearing threshold of rat ABR test ( *p<0.05, ** p<0.005, *** p<0.0005, # represents the comparison between Cis group and Control group).

[0023] Fig.11 The results of ABR test in rats.

[0024] Fig.12 The DPOAE test results of rats at different frequencies ( * p<0.05, ** p<0.005, *** p<0.0005, # represents the comparison between Cis group and Control group).

[0025] Fig.13 is the change of TNF-α content in rat cochlear tissue ( * p<0.05, ** p<0.005, *** p<0.0005, # represents the comparison between Cis group and Control group).

[0026] Fig.14 These are cochlear tissue sections of a rat model of cisplatin ototoxicity (A: cochlear HE-stained cross section 40X; B: cochlear HE-stained cross section 200X). DETAILED DESCRIPTION

[0027] The raw materials and equipment used in the present invention are all known products, which are obtained by purchasing commercially available products.

[0028] Example 1: Treatment of Cisplatin Ototoxicity with Anisodamine Hydrobromide Tablets

[0029] 1. Experimental methods

[0030] (1) Experimental animals

[0031] 48 British guinea pigs, half male and half female, weighing 200-250 g, agile, and with sensitive auricular reflexes. They were purchased from Chongqing Watson Biological Co., Ltd., with animal production license number: SCXK (Yu) 2021-003. The animals were kept in the SPF animal room of the School of Pharmacy of Chengdu University of Traditional Chinese Medicine, with animal experiment license number: SYXK (Chuan) 2020-0124. Animal experiments and disposal complied with the regulations on experimental animal management and the Ethics Committee of Chengdu University of Traditional Chinese Medicine, with ethics review number: 2024034.

[0032] (2) Experimental drugs and reagents

[0033] Anisodamine hydrobromide tablets were purchased from Chengdu No. 1 Pharmaceutical Co., Ltd. (H51023899, Chengdu, China);

[0034] Betahistine was purchased from Shanghai McLean Biochemical Technology Co., Ltd. (C16154557, Shanghai, China);

[0035] Cisplatin was purchased from Jiangsu Hansoh Pharmaceutical Group Co., Ltd. (H20 040813, Jiangsu, China).

[0036] (3) Animal models and groups

[0037] The ototoxicity model of guinea pigs was prepared. After locating the tympanic membrane under endoscopy, 50 μL of cisplatin was injected into the tympanic cavity of each group. After 3 hours, the guinea pigs showed symptoms such as behavioral changes, hearing loss, and decreased blood flow, which reached a peak after 6 hours and were tested.

[0038] Guinea pigs were randomly divided into 6 groups: control group (Control), cisplatin group (Cisplatin), betahistine group (Betahistine), low-dose anisodamine hydrobromide group (L-Ani HBr), medium-dose anisodamine hydrobromide group (M-AniHBr), and high-dose anisodamine hydrobromide group (H-Ani HBr), with 8 in each group. Five hours after modeling, the Betahistine group was given 8.24 mg / kg betahistine solution, and the L-Ani HBr / , M-Ani HBr / H-Ani HBr groups were given 2.575 mg / kg, 5.15 mg / kg, and 10.3 mg / kg anisodamine hydrobromide, respectively. The control group was given normal saline, and the model group was not given any drug.

[0039] (4) Behavioral testing

[0040] ① Nystagmus and head shaking

[0041] Observe the frequency of nystagmus and head shaking. Each observation period lasts 1 minute.

[0042] ②Head deviation

[0043] A straight line was drawn from the center of the sacrum to the center of the first thoracic vertebra, and another straight line was drawn from the tip of the nose to the middle of the top of the skull. The angle between these two extended lines was measured to determine the degree of head deviation.

[0044] ③ Air righting reflex

[0045] Place the guinea pig in a supine position and drop it onto a foam pad from a height of 30-40 cm. Score the animal's reaction as follows: 0 points, successful right turn and vertical landing. 1 point, face-to-face landing, but not smooth. 2 points, sideways landing, then right turn. 3 points, sideways landing, slowly turning. 4 points, right side up, failed right turn.

[0046] ④ Negative geotropism

[0047] Negative geotropism is an automatic, inexperienced reaction and directional movement to gravity cues that stimulates an abnormal position of the head and body, triggered by the vestibular and postural systems. The guinea pig was placed head down on a 40-degree slope 15 cm from the top of the slope (the sponge pad surface was inclined and covered with a thick towel). The time required for the guinea pig to turn 180° upward was recorded. Between each experiment, the animal rested for 30 seconds to reduce stress and fatigue. The maximum recording time was 15 seconds (3 recordings per guinea pig). The average of the three recordings was taken.

[0048] (5) Laser Speckle Imaging (LSI)

[0049] Laser speckle imaging is a full-field, quantitative, real-time optical method that has been used to monitor dynamic blood flow with high temporal and spatial resolution. The room temperature was controlled at 22-25°C. Guinea pigs were anesthetized with isoflurane. The auricle was gently attached to the slide with double-sided tape and saline was applied to the auricle. The laser speckle blood flowmeter was turned on and the focus was adjusted to obtain a clear image. The observation and recording time was 60 seconds. The baseline was stable in the first 30 seconds, and the average blood flow value was recorded in the last 30 seconds.

[0050] (6) Auditory electrophysiological test

[0051] The auditory brainstem response (ABR), distortion product otoacoustic emission (DPOAE) and compound action potential (CAP) of guinea pigs were measured in a quiet environment with an ambient noise less than 20 dB SPL using an auditory physiology system (RZ6, Tucker-Davis Technologies, Alachua, USA).

[0052] ① For ABR measurement, the reference electrode needle was inserted subcutaneously in the right earlobe, the recording electrode was inserted subcutaneously in the median cranial apex, and the ground electrode was inserted subcutaneously in the left earlobe. The speaker was placed at a calibrated distance in front of the guinea pig's interaural axis for click stimulation. The filter frequency was set to 300-3000 Hz, the stimulation rate was 21.1 times / second, and the superposition was set to 1024 times. The goal was to elicit a clear and reproducible wave II response threshold at an intensity of 90 dB.

[0053] ②DPOAE measurement, the otoacoustic emission probe is inserted into the external auditory canal of the guinea pig, completely closing the external auditory canal. The test frequencies used are 4, 8, 16 and 32kHz, and the frequency ratio between the two stimuli is set to f2 / f1=1.2. When the amplitude of 2f1-f2 is 6dB higher than the background noise, DPOAE is generated. The minimum intensity required to cause DPOAE is determined, representing the hearing threshold of the guinea pig.

[0054] ③CAP measurement, the recording electrode (silver wire electrode) is placed on the right eardrum, the reference electrode is placed under the skin of the right earlobe, and the ground electrode is placed under the skin of the left earlobe. When clicking sound stimulation, the filter frequency is set to 300-3000Hz, the stimulation rate is 21.1 times / second, and superposition is 1024 times. The test sound intensity starts from 90db and decreases by 5db in sequence, and the threshold of the CAP wave is recorded.

[0055] (7) Oxidative stress index

[0056] After anesthesia, blood was collected from the abdominal aorta of guinea pigs and allowed to stand at room temperature for 1 hour. The collected blood was centrifuged at 3000 rpm and 4°C for 15 minutes, and the supernatant was collected. Serum SOD (E-BC-K019-M, Elabscience), GSH (E-BC-K030-M, Elabscience), and MDA (E-EL-0060c, Elabscience) levels were measured.

[0057] (8) Statistical analysis

[0058] Data were expressed as mean ± SD using SPSS version 17.0 (SPSS, Inc., Chicago, IL, USA). One-way analysis of variance (ANOVA) was used to determine the statistical significance of differences between groups, followed by Student-Newman-Keuls test for multiple comparisons. P (two-tailed) < 0.05 was considered statistically significant.

[0059] 2. Experimental results

[0060] Effects of Ani HBr on behavior: Figure 1 As shown in the figure, compared with the control group, the head shaking frequency, nystagmus number, head deviation, air righting reflex score and negative ground tendency of guinea pigs in the model group were significantly increased (P<0.01). Compared with the model group, the betahistine group and different doses of Ani HBr were significantly or extremely significantly reduced (P<0.05 or P<0.01). However, there was no statistically significant difference in the head shaking frequency between the low-dose Ani HBr and the model group.

[0061] Effect of Ani HBr on blood flow: Figure 2 The results showed that the relative blood flow of guinea pigs in the model group was significantly lower than that in the control group (P<0.01). Compared with the model group, the relative blood flow of guinea pigs treated with different doses of Ani HBr increased significantly (P<0.01).

[0062] Effects of Ani HBr on hearing electrophysiology: Figure 3 , Figure 4 , Figure 5As shown, compared with the control group, the ABR latency, ABR threshold, and CAP in the model group were significantly increased (P<0.01). The ABR latency, ABR threshold, and CAP threshold of different doses of Ani HBr were lower than those in the model group (P<0.05 or P<0.01). There was no ABR threshold in the low-dose group (P>0.05). At 4000Hz, 8000Hz, 16000Hz, and 32000Hz, the DPOAE threshold in the model group was significantly higher than that in the control group (P<0.01). After treatment with Ani HBr and betahistine, except for the low-dose Ani HBr group, the DPOAE thresholds of each frequency were significantly lower than those in the model group (P<0.05 or P<0.01) ( Figure 6 ).

[0063] Effects of Ani HBr on oxidative stress: Figure 7 It can be seen that the T-SOD and GSH concentrations of guinea pigs in the model group were significantly or extremely significantly lower than those in the control group (P<0.05 or P<0.01), and the MDA concentration was significantly higher than that in the control group (P<0.01). Compared with the model group, the GSH concentration in the AniHBr group increased, and the MDA concentration decreased (P<0.05 or P<0.01).

[0064] The above results show that Ani HBr can significantly improve cisplatin-induced ototoxicity in guinea pigs. Ani HBr plays an important role in preventing ototoxicity by improving behavioral performance and hearing impairment, promoting blood flow, and inhibiting oxidative stress. As the dose of Ani HBr increases, the effect of improving ototoxicity is better.

[0065] Example 2: Treatment of Cisplatin Ototoxicity with Anisodamine Hydrobromide Injection

[0066] 1. Experimental methods

[0067] (1) Experimental animals

[0068] SD rats, half male and half female, weighing 200-250 g, were purchased from Sibeifu (Beijing) Biotechnology Co., Ltd., Animal Production License No.: SCXK (Beijing) 2019-0010. The animals were kept in the SPF animal room of the School of Pharmacy of Chengdu University of Traditional Chinese Medicine, Animal Experiment License No.: SYXK (Sichuan) 2020-0124, with a day and night cycle of 12 / 12 hours. The experiment was approved by the Animal Ethics Committee of Chengdu University of Traditional Chinese Medicine, Ethics Review No.: 2024034.

[0069] (2) Experimental Materials

[0070] Anisodamine hydrobromide injection, Chengdu No. 1 Pharmaceutical Co., Ltd., product batch number 29230902;

[0071] Dexamethasone injection, Suicheng Pharmaceutical Co., Ltd., product batch number 22306041;

[0072] Cisplatin injection, Jiangsu Hausen Pharmaceutical Group Co., Ltd., product batch number 601231007;

[0073] TNF-α kit, Wuhan Elaruite Biotechnology Co., Ltd., batch number DP0282645110.

[0074] (3) Model establishment and grouped drug administration

[0075] Thirty-six rats were divided into six groups: Control group, Cis group, Cis+Dex group, Cis+ANI (2 mg) group, Cis+ANI (4 mg) group and Cis+ANI (8 mg) group.

[0076] After isoflurane anesthesia, the rats in the control group were injected with 50 μL of 0.9% saline into the right ear cavity, and the rats were kept lying with their right ears upward for 30 min. After isoflurane anesthesia, the rats in the other groups were injected with 50 μL of 5 mg / ml cisplatin injection into the right ear cavity, and the rats were kept lying with their right ears upward for 30 min to prepare the unilateral vestibular dysfunction model.

[0077] Each group received intraperitoneal administration 30 minutes, 24 hours, and 48 hours after the tympanic injection of cisplatin. The Control group was injected with 0.9% saline; the Cis group was injected with 0.9% saline; the Cis+Dex group was injected with 20 mg / kg dexamethasone injection; and the Cis+ANI (2 mg / 4 mg / 8 mg) group was injected with the corresponding dose of scopolamine hydrobromide injection.

[0078] 60 minutes after administration on the third day, serum samples of rats in each group were collected and the right cochlea was isolated for later use.

[0079] (4) Behavioral testing

[0080] Behavioral testing was carried out 48 hours after modeling, and the specific scoring content included:

[0081] 1) Head deviation: The head of rats with vestibular damage will tilt to one side, which is related to asymmetric changes in muscle tone;

[0082] 2) Tail-hanging reflex: When normal rats are lifted from the table by the tail, their forelimbs will stretch forward, while when rats with unilateral vestibular dysfunction are lifted from the table by the tail, their whole bodies will rotate from slight to strong;

[0083] 3) Nystagmus: The eyes of rats with vestibular dysfunction will jump up and down involuntarily;

[0084] 4) Balance beam: The rats were scored based on their performance on the balance beam (4 points for each item, with a full score of 16 points). See Table 1 for specific scoring criteria.

[0085] Table 1 Behavioral scoring table of rats with vestibular dysfunction induced by cisplatin

[0086]

[0087] (5) Hearing test

[0088] The auditory brainstem response (distortion product otoacoustic emission, ABR) and distortion product otoacoustic emission (distortion product otoacoustic emission, DPOAE) of rats in each group were tested using an auditory physiology workstation (RZ6, Tucker-Davis Technologies, USA). Rats with abnormal hearing were excluded before ABR and DPOAE tests.

[0089] The ABR detection method is as follows: 48 hours after modeling, rats in each group were given drugs and anesthetized with isoflurane and placed on a 37°C electric blanket. Needle electrodes were connected, the recording electrode was connected to the middle of the line connecting the two ears, the reference electrode was connected to the back of the right ear, and the ground electrode was connected to the back of the contralateral ear. The BioSigRZ software was opened and the ABR parameters were set (stimulus sound: click sound, stimulation rate: 21.1 times / s, bandpass filter: high pass 300Hz, low pass 3000Hz, notch (NT) 50Hz, observation time: 0-10ms, superposition times: 512 times, magnification: 100x). The entire detection process was carried out in a soundproof room. Subsequently, the ABR of rats in each group was detected in an intensity range of 0-90dB SPL, with an attenuation interval of 10dB. When approaching the threshold, the attenuation interval was adjusted to 2dB, so that the minimum intensity to induce a stable and repeatable III wave was the ABR response threshold.

[0090] The DPOAE detection method is as follows: 48 hours after modeling, rats in each group were given drugs and anesthetized with isoflurane and placed on a 37°C electric blanket. The DPOAE detection was performed using the RZ6 TDT Auditory Physiological Workstation equipment, and the entire operation was performed in an electrostatically shielded soundproof room. The frequencies of the initial pure tone F1 and F2 were selected, and the frequency ratio F2:F1=1.2. The initial sound pressure levels were L1 and L2, and L1=L2. The number of superpositions was 512 times, and the DP value was 6dB higher than the background noise (i.e., induced). Fc was selected as 4KHz, 8K Hz, 16KHz, and 32kHz, respectively. The DPOAE of rats in each group was detected at each frequency with an intensity range of 0-90dB SPL, and the attenuation interval was 10dB. When approaching the threshold, the attenuation interval was adjusted to 5dB to induce a stable and repeatable DP as the reaction threshold of DPOAE at the current frequency.

[0091] (6) TNF-α detection

[0092] According to the instructions of the ELISA kit, the TNF-α concentration in the serum of rats in each group was detected, and the results were measured using an ELISA reader (ABS plus, Shanghai Meigu Molecular, China).

[0093] (7) H&E staining

[0094] The right cochlea was removed and fixed in 4% paraformaldehyde solution for 48 hours. The fixed cochlea was removed and added with slow decalcification solution until the cochlear tissue was completely decalcified. The decalcified cochlear tissue was dehydrated under increasing ethanol concentrations and embedded in paraffin. The tissue was then sliced ​​into 3 μm slices, stained with H&E, and observed under a light microscope to record the histopathological information.

[0095] (8) Data analysis

[0096] All data were processed on GraphPad Prism 8 software. Statistical differences among multiple groups were determined by analysis of variance followed by Dunnett's test or Tukey's test. All values ​​are expressed as mean ± standard deviation, and a level of P < 0.05 was considered statistically significant.

[0097] 2. Experimental results

[0098] (1) Anisodamine hydrobromide injection can alleviate behavioral abnormalities caused by cisplatin ototoxicity

[0099] The present invention scored each group of rats according to the behavioral scoring table (Table 1), and the results ( Figure 8 , 9) showed that the tail-hanging reflex of the rats in the Control group was normal, while the tail-hanging reflex of the rats in the Cis group was severe, with a score of 4 points. After administration, the tail-hanging reflex caused by the tympanic injection of Cis could be effectively relieved in each drug-treated group; the balance beam results showed that it was difficult for the rats in the Cis group to pass the balance beam, while the rats in each drug-treated group could effectively pass the balance beam, and the score could be reduced to 1 point; the head deviation results showed that the head deviation of the rats in the Cis group was severely tilted, and the degree of head tilt of the rats in each drug-treated group was reduced; the nystagmus results showed that the number of nystagmus of the rats in the Cis group exceeded 100 times / min, and the number of nystagmus of the rats in each drug-treated group was significantly reduced compared with that in the Cis group; in terms of the total score, the behavioral abnormalities of the rats in the Cis group were extremely serious compared with those in the Control group, and the abnormal behavior of the model rats could be significantly alleviated after administration of ANI HBr.

[0100] In conclusion, low, medium and high doses of anisodamine hydrobromide injection can effectively alleviate the behavioral abnormalities in rats induced by cisplatin.

[0101] (2) Anisodamine hydrobromide injection can reduce hearing loss caused by cisplatin ototoxicity

[0102] In order to explore whether anisodamine hydrobromide injection has a protective effect on hearing loss caused by cisplatin, the present invention performed ABR and DPOAE tests on rats in each group. ABR test results ( Fig.10 , 11 ) showed that the hearing of rats in the Control group was about 35dB, while the hearing of the Cis group was extremely reduced, with the hearing threshold reduced to about 65dB. Each drug-treated group had a significant therapeutic effect on hearing loss caused by cisplatin, and could restore the hearing threshold to about 55dB, indicating that scopolamine hydrobromide injection has a significant protective effect on hearing damage caused by cisplatin. DPOAE results ( Fig.12 ) showed that low-frequency and high-frequency hearing loss occurred after intratympanic injection of Cis, and scopolamine hydrobromide injection had a protective effect on the low-frequency band of rats with cisplatin-induced ototoxicity.

[0103] (3) Anisodamine hydrobromide injection can reduce the level of inflammatory factor TNF-α in cochlear tissue

[0104] In order to determine whether anisodamine hydrobromide injection can reduce inflammation caused by cisplatin, the present invention used Elisa kit to detect the content of TNF-α in the cochlear tissue of rats in each group. The results showed that anisodamine hydrobromide injection can effectively reduce the level of TNF-α in the cochlear tissue of rats with ototoxicity caused by cisplatin ( Fig.13 ).

[0105] (4) Anisodamine hydrobromide injection can protect the apoptosis of cochlear hair cells induced by cisplatin

[0106] Cochlear HE staining results ( Fig.14 ) showed that the cochlear HE staining results showed that after Cis intratympanic injection, a large number of cochlear hair cells were lost and died in the Cis group, and the inner ear structure was severely damaged; after the injection of scopolamine hydrobromide, the inner ear structure was relatively intact compared with the Cis group, and the loss and death of hair cells were alleviated. Among the different dose groups, it was also found that the effect of the ANI4mg group was better than that of the ANI8mg group.

[0107] The above results show that after administration, anisodamine hydrobromide injection can protect the low-frequency hearing loss of UVD rats, counteract the cochlear toxicity caused by cisplatin, slow down the hearing threshold, and reduce the level of inflammation in the cochlear tissue. Anisodamine hydrobromide injection can effectively relieve the symptoms of cisplatin ototoxicity induced by transtympanic injection and has a significant therapeutic effect.

[0108] In summary, the present invention provides the use of anisodamine hydrobromide in the preparation of drugs for preventing and / or treating cisplatin ototoxicity. The present invention first discovered that anisodamine hydrobromide tablets can significantly improve ototoxicity caused by cisplatin, improve hearing impairment, promote blood flow, and inhibit oxidative stress, and anisodamine hydrobromide injection can improve ototoxic hearing damage caused by cisplatin, and has anti-inflammatory and cochlear hair cell protection effects. Anisodamine hydrobromide has broad application prospects in the preparation of drugs for preventing and / or treating cisplatin ototoxicity.

Claims

1. Use of anisodamine hydrobromide in the preparation of a drug for treating cisplatin ototoxicity.

2. The use according to claim 1, characterized in that The medicine is a pharmaceutical preparation prepared by taking anisodamine hydrobromide as an active ingredient and adding pharmaceutically acceptable auxiliary materials.

3. The use according to claim 2, characterized in that: The pharmaceutical preparation is an oral preparation or an injection preparation.

4. The use according to claim 3, characterized in that The oral preparations are tablets, granules and capsules.

5. The use according to claim 3, characterized in that: The injection preparation is an injection solution or a powder injection.

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